IntroductionFor many years, the science of schizophrenia seemed stuck at the level
of neurotransmitters and receptors. Decades of research had apparently
proven the singular importance of dopamine and dopamine receptors to the
understanding of schizophrenia and its treatment. Unfortunately, this
awareness had brought us only so far in understanding the underlying pathophysiology
and the ways in which we could improve outcomes in our patients. While
the positive symptoms of schizophrenia, including hallucinations, delusions,
and disorganized thinking, were often effectively ameliorated with typical
antipsychotics -- with a singular mechanism action of D2 blockade, the
negative and cognitive symptoms were left untouched and understudied.

The identification of clozapine as an effective treatment for previously
untreatable patients with schizophrenia brought a paradigm shift in several
important areas. First, other neurotransmitters, specifically serotonin,
became important in the understanding of schizophrenia. Second, the benefits
of clozapine for negative and cognitive symptoms led to an increased realization
of their importance in affecting quality of life and other important outcomes.
The evolution in understanding of the pathophysiology of schizophrenia,
however, remained at the level of neurotransmitters and their receptors.

Analogous to the era of phrenology, the "bumps" that were seen
on neurons only hinted at the dysfunction in the flesh below. With advances
in techniques of molecular genetics, functional neuroimaging, and other
research methods, the calvaria has been removed and the underlying function
of the brain is becoming increasingly better understood. An emerging theme
in schizophrenia research that was evident at this year's American Psychiatric
Association annual meeting is that parallel lines of research are rapidly
progressing beyond the level of simple transmitters to define neuroanatomical
and neurophysiological circuits that lie at the heart of cerebral dysfunction
in schizophrenia.

Nicotinic Receptor Model
To further broaden the number of neurotransmitters found to be important
in understanding the pathophysiology and the complex neurocircuitry in
schizophrenia, research over the last several years has provided clues
to the impact of dysfunction of both cholinergic and glutamatergic neurotransmitter
systems. The work of Robert Freedman, MD,[1] Chairman of the Department
of Psychiatry at the University of Colorado Health Sciences Center, Denver,
has progressed from early studies showing deficits in auditory information
processing in schizophrenia to a well-described model of cortical dysfunction
in schizophrenia related to dysfunction of a specific nicotinic receptor
using molecular genetic techniques. By tracing the deficits in auditory
information processing through families that included patients with schizophrenia
and unaffected relatives, Dr. Freedman's group was able to show that a
relatively common genetic mutation in nicotinic receptors, found in 10%
of the population, caused difficulties in sensory gating and could be
a predisposing factor for the impaired cognition and psychosis seen in
schizophrenia. His research indicates a deficit in inhibitory interneuronal
function, involving the alpha7-nicotinic receptor, as an integral feature
of the altered neurocircuitry in schizophrenia. Such impaired nicotinic
receptor function could be at the heart of the dramatically increased
use of nicotine in patients with schizophrenia.

Glutamate Model
With all the emphasis in psychiatric research on neurotransmitters, it
seems odd that the most prevalent and possibly most important neurotransmitter
of them all was ignored. Glutamate, by virtue of the fact that it is found
in high concentrations in the brain with much of it not acting as a neurotransmitter,
was difficult to see as a neurotransmitter at all. However, it is now
widely understood that glutamate is the most prevalent excitatory neurotransmitter
in the brain and that dysfunction of glutamate receptors, which are likely
present on every cell in the brain, lies at the heart of many neurologic,
and possibly psychiatric, diseases.

Carol Tamminga, MD,[2] Professor of Psychiatry and Pharmacology at the
University of Maryland School of Medicine, Baltimore, has published several
studies measuring effects of certain compounds on a specific glutamate
receptor, the NMDA receptor. The NMDA receptor is most known for its involvement
as a mechanism of action of the hallucinogenic properties of phencyclidine,
or PCP. Dr. Tamminga and colleagues have used PCP and ketamine in humans
as a model of the pathophysiology of schizophrenia. PCP and ketamine were
both initially used as anesthetic agents, and ketamine is still commonly
used in dental procedures. Both PCP and ketamine antagonize the action
of the NMDA receptor by blocking the ion channel and can cause perceptual
disturbance and cognitive dysfunction similar to that seen in schizophrenia.
In addition, when these compounds are given to patients with schizophrenia
their symptoms are magnified. Using positron emission tomography (PET)
studies, Dr. Tamminga's group has shown that ketamine increases regional
cerebral blood flow in the anterior cingulate cortices and decreases flow
in the hippocampus and cerebellum, all areas that had previously been
shown to be abnormal in schizophrenia. A hypoglutamatergic state beginning
in the hippocampus could inhibit excitatory transmission to the anterior
cingulate and temporal cortex. The complicated neurocircuitry could include
GABA and cholinergic interneurons that regulate pyramidal cell firing
as well, thereby expanding pharmacological targets for treatment to glutamatergic,
cholinergic, and GABA-ergic modulators.

Role of Dopamine
Returning to the importance of dopamine in the pathophysiology of schizophrenia,
Daniel Weinberger, MD,[3] Chief of the Clinical Brain Disorders Branch
at the National Institute of Mental Health, has conducted research into
the importance of catechol-O-methyl transferase, or COMT, in the pathophysiology
of schizophrenia. COMT is an enzyme that degrades dopamine in the synaptic
cleft. Interestingly, unlike the striatum, the prefrontal cortex has no
dopamine transporters. Dopamine transporters are reuptake sites similar
to those found on serotonin receptors. When these reuptake sites are blocked,
like with serotonin reuptake inhibitors, or don't exist, as is the case
in the prefrontal cortex for dopamine, the effects of neurotransmitter-degrading
enzymes are extremely important. Hence the contraindication of concurrent
serotonin reuptake inhibitors and monoamine oxidase inhibitor use. Therefore,
the effect of COMT in the action of dopamine in the prefrontal cortex
is substantial. In fact, animal studies have shown that COMT is responsible
for more than 60% of dopamine degradation in the prefrontal cortex. And
dopamine action in the prefrontal cortex is supremely important for cognition.
Dopamine activity in the prefrontal cortex, through studies done in patients
with Parkinson's disease, has been shown to dramatically increase the
"efficiency" of neurocognitive performance. This, in essence,
allows the brain to focus more of its energy on brain regions that are
important for processing information. This effect of dopamine, and its
disruption, is possibly responsible for the deficits in attention and
executive functioning commonly found in patients with schizophrenia.

Genetic Techniques
Using molecular genetic techniques similar to those used by Dr. Freedman,
Dr. Weinberger and colleagues[3] have shown that a single point mutation
in the COMT gene causes a 75% reduction in the activity of COMT. This
genetic "defect," which increases dopamine activity in the prefrontal
cortex, has been shown, using the Wisconsin Card Sort Test, to significantly
improve executive functioning. In fact, this "defect," which
is responsible for 4% of the human variation of attention and executive
functioning and is not found in great apes, was proposed as a potential
factor in the evolution of the cortex, and, therefore, of mankind itself.
And the gene encoding the more effective form of COMT has been shown to
be significantly more prevalent in patients with schizophrenia than in
normal controls. This line of evidence makes a convincing argument that
the gene encoding the more effective form of COMT is a susceptibility
gene for schizophrenia. With the elucidation of the importance of COMT,
another target for psychopharmacology is delineated.

Glia and White Matter
With all the focus on neurons, it is easy to forget that the vast majority
of the cells in our brains are not neurons, but glia. Glia, including
astrocytes and oligodendrocytes, make up more than half the brain's weight
and outnumber neurons by a factor of more than 101. Their actions of support
to neurons are crucial to proper brain function. Astrocytes are believed
to provide structural support for the neurons of the brains and aid in
the repair of neurons following damage to the brain. Oligodendrocytes
produce myelin, which surrounds the axons of many neurons and is the identifying
component of white matter. Taking the research into the pathophysiology
of schizophrenia into a heretofore-neglected area, Kenneth L. Davis, MD,[4]
Chairman of the Department of Psychiatry at Mount Sinai School of Medicine,
New York, NY, presented data indicating that alterations in white matter
may be intimately involved.

Moving forward from an atheoretical presupposition, measuring gene expression
changes detected by microarray DNA-chip analysis of postmortem tissue
from the dorsolateral prefrontal cortex of patients with schizophrenia
-- analogous to a scientifically sound "fishing expedition"
into altered genetic expression, Dr. Davis found that one can differentiate
schizophrenic from normal brains solely on the basis of expression of
myelin genes. Following this exciting finding, several investigators have
utilized different methods to show the dramatic damage to oligodendrocytes
in the brains of patients with schizophrenia. Not only are oligodendrocyte
counts in functionally important areas of the cortex significantly reduced,
but electron microscope findings show that such areas exhibit abnormal
inclusions between myelin sheath lamellae, showing evidence for cellular
dysfunction. Anisotropy, a measure of the coherence of white matter, has
also been shown to be reduced in frontal and temporal lobes of patients
with schizophrenia. Such "frayed wires" are further evidence
for altered neuronal structure and connectivity in schizophrenia.

Given this, dramatic alterations in oligodendrocyte function appear to
be present in schizophrenia, with reduced numbers, impaired function,
and disrupted cytoarchitecture. Decades of research have consistently
shown increased ventricular size in the brains of people with schizophrenia,
but reductions in gray matter volume have been small and inconsistently
found, outside of specific thalamic nuclei. Could it be that, all along,
the lost brain volume in schizophrenia has come from loss of white matter?

One exciting possibility that could link several of these parallel lines
of research involves glutamate hyperactivity. Bita Moghaddam, PhD,[5]
Associate Professor in Psychiatry at Yale University, New Haven, Connecticut,
published an important paper in 1997 showing that ketamine, an NMDA antagonist,
actually increased glutamate outflow in the prefrontal cortex to non-NMDA
receptors. Overactivation of AMPA and kainate receptors, 2 important non-NMDA
glutamate receptors, has been linked to subsequent excitotoxic oligodendroglial
death.[6] Thus, endogenous alterations in the glutamate system, mimicked
by drugs such as PCP and ketamine as in the work by Dr. Tamminga, could
lead to excessive glutamate release onto oligodendrocytes -- leading to
impaired function, cell death, and loss of white matter.

Such a model that includes both known neurophysiological and neuroanatomical
deficits found in the brains of people with schizophrenia offers hope
that we are ever closer to answering a question deserving of the Nobel
prize: what is the pathophysiology of schizophrenia and how do we treat
it?